This section reviews the solubility and permeability of various substances, including medicines, food additives, and pollutants, which are often hydrophobic and can cross biological membranes. The membrane permeability, influenced by factors such as lipid rafts, is generally modeled using the partition coefficient (log P). The solubility of active pharmaceutical ingredients (APIs), particularly acidic analgesics, is significantly influenced by basic and hydrophobic compounds. For instance, lidocaine enhances the solubility of indomethacin and other analgesics, while more hydrophobic compounds generally reduce it. The complexity of solubility behavior is highlighted, emphasizing the need to investigate solute–solvent interactions further. Dissolving APIs in their solid form involves supersaturation, which can be managed through excipient strategies to enhance bioavailability. The “spring” effect facilitates rapid dissolution followed by recrystallization, while the “parachute” effect prolongs supersaturation by preventing recrystallization. Controlling these effects is crucial for maintaining the therapeutic concentrations of APIs. Lidocaine and diltiazem affect the solubility of α-aryl-propionic and α-aryl-acetic acid-type analgesics through enthalpy–entropy compensation, whereas oxybuprocaine and propranolol do not influence oxicam-type ones. Additionally, it reports the protective effects of lidocaine and dibucaine against lipid peroxidation in liposomal membranes, suggesting the need for further research into drug–membrane interactions. This study highlights the importance of exploring the interaction between the structural characteristics of the drug solution and the membranous phase separation to optimize therapeutic efficacy.